Influenza (flu) is a contagious respiratory disease caused by influenza virus infection. Annual flu outbreaks in the United States affect 5-20% of the population (CDC Fact Sheet, 2006). Flu complications such as bacterial pneumonia, ear and/or sinus infections, dehydration and worsening of chronic medical conditions can result in severe illness and even death. Yearly flu vaccinations are recommended for preventing the flu, particularly for high-risk individuals (e.g., children, elderly, etc.) and their caretakers (e.g., health care workers).
Currently used inactivated influenza (flu) virus vaccines are the product of the 6+2 re-assortment containing hemagglutinin (HA) and neuraminidase (NA) genes from the vaccine target strain and the remaining genes from A/Puerto Rico/8/34-H1N1 (PR8). These vaccines display suboptimal efficacy as determined by the finding that approximately 25%-50% of immunized individuals (in particular elderly populations) contract the disease during the flu season (Webster, Vaccine, 18:1686, 2000). The need for increasing immunogenicity of flu vaccines is an urgent matter because of the risk for pandemic outbreaks of the H5N1 avian influenza virus. The avian flu virus causes severe and often fatal disease in humans characterized by fulminant pneumonia and multi-organ failure (De Jong et al., Nat Med, 12:1203, 2006). The virus displays high replication efficacy, broad tissue tropism and systemic replication, which is likely associated with the high virulence of this virus (De Jong et al., supra, 2006). The avian flu virus has caused the recently documented human H5N1 infections. However, there is a significant risk that additional mutations in H5N1 will convert the virus into an infectious form able to spread from human to human. Therefore, the development of an effective prophylactic vaccine against both the seasonal infectious wild type virus and the H5N1 avian virus is needed to prevent future pandemics.
Based on a wide body of research that has been performed on flu vaccines it has been determined that an effective flu vaccine, will have to achieve several immunological goals including: 1) eliciting an anti-HA reactive antibody response to prevent infection of cells (including respiratory tract cells) by the pathogenic virus; and 2) eliciting a broad cross-protective antibody response against the conserved M2e ectodomain of the ion channel M2 protein for inducing antibody mediated destruction of infected cells expressing large amounts of the M2 protein; and 3) eliciting a broad cross-protective cellular immune response against flu virus nucleoprotein (NP) for including cytotoxic T cells (CTL) mediated destruction of infected cells presenting NP peptides (Black et al., J Gen Virol, 74:143-146, 1993; and Flynn et al., Proc Natl Acad Sci USA, 96:8597, 1999). The broad immune response to M2e and to NP is feasible since these proteins are conserved in various flu virus strains, unlike HA which differs significantly in different strains (Black et al., supra, 1993; and Riberdy et al., J Virol, 73:1453, 1999). Since the M2 protein is present in only small amounts in subunit vaccines (Zhang et al., Mol Immunol, 43: 2195, 2006), and since NP is non-immunogenic in subunit vaccines, the immunogenicity of recombinant M2e and NP has been found to be suboptimal (Mozdzanowska et al., Vaccine, 21: 2616, 2003). Such low immunogenicity is usually associated with poor uptake of the vaccine by antigen presenting cells (APC) at the inoculation site.
Thus, compositions and methods for increasing the immunogenicity of inactivated flu virus are needed in the art. Likewise, compositions and methods for increasing the immunogenicity of other microbial antigens are desirable.